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Gliotoxin (GT), a secondary metabolite and virulence factor of the fungal pathogen Aspergillus fumigatus, suppresses innate immunity and supports the suppression of host immune responses. Recently, we revealed that GT blocks the formation of the chemotactic lipid mediator leukotriene (LT)B4 in activated human neutrophils and monocytes, and in rodents in vivo, by directly inhibiting LTA4 hydrolase. Here, we elucidated the impact of GT on LTB4 biosynthesis and the entire lipid mediator networks in human M1‐ and M2‐like monocyte‐derived macrophages (MDMs) and in human tissue‐resident alveolar macrophages. In activated M1‐MDMs with high capacities to generate LTs, the formation of LTB4 was effectively suppressed by GT, connected to attenuated macrophage phagocytic activity as well as human neutrophil movement and migration. In resting macrophages, especially in M1‐MDMs, GT elicited strong formation of prostaglandins, while bacterial exotoxins from Staphylococcus aureus evoked a broad spectrum of lipid mediator biosynthesis in both MDM phenotypes. We conclude that GT impairs functions of activated innate immune cells through selective suppression of LTB4 biosynthesis, while GT may also prime the immune system by provoking prostaglandin formation in macrophages. [ABSTRACT FROM AUTHOR]

Clinical studies have demonstrated that IL-4, a type 2 cytokine, plays an important role in the pathogenesis of chronic rhinosinusitis and eosinophilic asthma. However, the direct effect of IL-4 on eosinophils remains unclear. We aimed to elucidate the inflammatory effects of IL-4 on the functions of human eosinophils. A multiomics analysis comprising transcriptomics, proteomics, lipidomics, quantitative RT-PCR, and flow cytometry was performed by using blood eosinophils from healthy subjects stimulated with IL-4, IL-5, or a combination thereof. Transcriptomic and proteomic analyses revealed that both IL-4 and IL-5 upregulate the expression of γ-gultamyl transferase 5, a fatty acid–metabolizing enzyme that converts leukotriene C 4 into leukotriene D 4. In addition, IL-4 specifically upregulates the expression of IL-1 receptor-like 1 (IL1RL1), a receptor for IL-33 and transglutaminase-2. Additional transcriptomic analysis of cells stimulated with IL-13 revealed altered gene expression profiles, characterized by the upregulation of γ-gultamyl transferase 5, transglutaminase-2, and IL1RL1. The IL-13–induced changes were not totally different from the IL-4–induced changes. Lipidomic analysis revealed that IL-5 and IL-4 additively increased the extracellular release of leukotriene D 4. In vitro experiments revealed that STAT6 and IL-4 receptor-α control the expression of these molecules in the presence of IL-4 and IL-13. Analysis of eosinophils derived from patients with allergic disorders indicated the involvement of IL-4 and IL-13 at the inflamed sites. IL-4 induces the proallergic phenotype of IL1RL1high eosinophils, with prominent cysteinyl leukotriene metabolism via STAT6. These cellular changes represent potential therapeutic targets for chronic rhinosinusitis and eosinophilic asthma. [ABSTRACT FROM AUTHOR]

Treatment of tuberculosis (TB) is faced with several challenges including the long treatment duration, drug toxicity and tissue pathology. Host‐directed therapy provides promising avenues to find compounds for adjunctively assisting antimycobacterials in the TB treatment regimen, by promoting pathogen eradication or limiting tissue destruction. Eicosanoids are a class of lipid molecules that are potent mediators of inflammation and have been implicated in aspects of the host response against TB. Here, we have explored the blood transcriptome of pulmonary TB patients to understand the activity of leukotriene B4, a pro‐inflammatory eicosanoid. Our study shows a significant upregulation in the leukotriene B4 signalling pathway in active TB patients, which is reversed with TB treatment. We have further utilized our in‐house network analysis algorithm, ResponseNet, to identify potential downstream signal effectors of leukotriene B4 in TB patients including STAT1/2 and NADPH oxidase at a systemic as well as local level, followed by experimental validation of the same. Finally, we show the potential of inhibiting leukotriene B4 signalling as a mode of adjunctive host‐directed therapy against TB. This study provides a new mode of TB treatment along with mechanistic insights which can be further explored in pre‐clinical trials. [ABSTRACT FROM AUTHOR]

Prostaglandin E2 (PGE2) is a recognized inhibitor of granulocyte functions. However, most of the data supporting this was obtained when available pharmacological tools mainly targeted the EP2 receptor. Herein, we revisited the inhibitory effect of PGE2 on reactive oxygen species production, leukotriene biosynthesis, and migration in human neutrophils. Our data confirm the inhibitory effect of PGE2 on these functions and unravel that the effect of PGE2 on human neutrophils is obtained by the combined action of EP2 and EP4 agonism. Accordingly, we also demonstrate that the inhibitory effect of PGE2 is fully prevented only by the combination of EP2 and EP4 receptor antagonists, underscoring the importance of targeting both receptors in the effect of PGE2. Conversely, we also show that the inhibition of ROS production by human eosinophils only involves the EP4 receptor, despite the fact that they also express the EP2 receptor. [ABSTRACT FROM AUTHOR]

Candida albicans causes opportunistic infections ranging from mucosal mycoses to life‐threatening systemic infections in immunocompromised patients. During C. albicans infection, leukotrienes and prostaglandins are formed from arachidonic acid by 5‐lipoxygenase (5‐LOX) and cyclooxygenases, respectively to amplify inflammatory conditions, but also to initiate macrophage infiltration to achieve tissue homeostasis. Since less is known about the cellular mechanisms triggering such lipid mediator biosynthesis, we investigated the eicosanoid formation in monocyte‐derived M1 and M2 macrophages, neutrophils and HEK293 cells transfected with 5‐LOX and 5‐LOX‐activating protein (FLAP) in response to C. albicans yeast or hyphae. Leukotriene biosynthesis was exclusively induced by hyphae in neutrophils and macrophages, whereas prostaglandin E2 was also formed in response to yeast cells by M1 macrophages. Eicosanoid biosynthesis was significantly higher in M1 compared to M2 macrophages. In HEK_5‐LOX/FLAP cells only hyphae activated the essential 5‐LOX translocation to the nuclear membrane. Using yeast‐locked C. albicans mutants, we demonstrated that hyphal‐associated protein expression is critical in eicosanoid formation. For neutrophils and HEK_5‐LOX/FLAP cells, hyphal wall protein 1 was identified as the essential surface protein that stimulates leukotriene biosynthesis. In summary, our data suggest that hyphal‐associated proteins of C. albicans are central triggers of eicosanoid biosynthesis in human phagocytes. [ABSTRACT FROM AUTHOR]

Background: Montelukast (MTK), a potent antagonist of cysteinyl leukotriene receptor 1, has shown therapeutic promise for the treatment of neuropsychiatric disorders. Delirium, a common complication in critically ill patients, lacks effective treatment. This study aims to explore the impact of pre-intensive care unit (ICU) MTK use on in-hospital delirium incidence and, subsequent, prognosis in critically ill patients. Methods: A retrospective cohort study (n = 6344) was conducted using the MIMIC-IV database. After propensity score matching, logistic/Cox regression, E-value sensitivity analysis, and causal mediation analysis were performed to assess associations between pre-ICU MTK exposure and delirium and prognosis in critically ill patients. Results: Pre-ICU MTK use was significantly associated with reduced in-hospital delirium (OR: 0.705; 95% CI 0.497–0.999; p = 0.049) and 90-day mortality (OR: 0.554; 95% CI 0.366–0.840; p = 0.005). The association was more significant in patients without myocardial infarction (OR: 0.856; 95% CI 0.383–0.896; p = 0.014) and could be increased by extending the duration of use. Causal mediation analysis showed that the reduction in delirium partially mediated the association between MTK and 90-day mortality (ACME: −0.053; 95% CI −0.0142 to 0.0002; p = 0.020). Conclusions: In critically ill patients, MTK has shown promising therapeutic benefits by reducing the incidence of delirium and 90-day mortality. This study highlights the potential of MTK, beyond its traditional use in respiratory disease, and may contribute to the development of novel therapeutic strategies for delirium. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 is associated with a cascade of inflammatory responses potentially lead to devastating outcomes. Objectives: The current study aims to investigate the efficacy of montelukast, a leukotriene receptor antagonist (LTRA), on laboratory parameters in COVID-19 infection. Patients and Methods: The current randomized clinical trial (RCT) conducted on 67 patients with moderate-to-severe COVID-19 pneumonia in 2020-2021. All patients received treatments according to the national guidelines, while the case group additionally applied 10 mg montelukast for 14 days. The clinical disease improvement and laboratory data (complete blood cells count and differentiation, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), D-dimer, blood urea nitrogen (BUN), creatinine (Cr), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) were assessed within two weeks after the infection and compared between the groups. Results: Baseline assessed parameters did not differ between the groups (P>0.05). A significant decrease in pulse rate, also in normal ranges, was notified in the montelukast-treated group compared with the baseline (P=0.001) and with controls (P=0.033); however, other vital signs were not statistically different (P>0.05). CRP (P

Objective:Triple negative breast cancer (TNBC) has high relapse rates due to dysregulated inflammatory signaling pathways and significant changes in the tumor microenvironment, probably influencing the failure of several therapies. The Cysteinyl Leukotriene Receptor 1 (CYSLTR1), a leukotriene modulator of inflammation, has been shown to play an important role in cancer pathogenesis and survival but few studies have been reported on its role in breast cancer.Materials and Methods:The present work was conducted using publicly available platforms that have omics data to assess the clinical potential of CYSLTR1 expression and its prognostic validation in large cohorts of samples from breast cancer patients. Web platforms containing clinical information, RNA-seq and protein data were selected to perform in silico analyses of the potential marker CYLSTR1. Added together, the platforms included modules for correlation, expression, prognosis, drug interactions, and construction of gene networks.Results:Kaplan–Meier curves revealed that reduced levels of CYSLTR1 corresponded to an unfavorable outcome for overall survival (p

Background: Pregnancy is a physiological state in which the female body undergoes a series of changes and adaptations to provide the best possible conditions for the growth and development of the forming baby. The internal adaptations that take place lead to the production of inflammation, which is necessary for the initial and final stages of pregnancy (embryo implantation and induction of labor). Gestational diabetes mellitus is considered to be the most common pathology during this period. However, many more serious health complications can arise, which include pre-eclampsia, fetal stunting, and preterm labor. The purpose of this study was to analyze the impact of the levels of individual eicosanoids on the course of normal pregnancy and the possibility of pathologies including gestational diabetes and pre-eclampsia. Methods: Sixty-nine pregnant women who were overweight or obese before and during pregnancy were studied. Eicosanoids were extracted as appropriate and then determined using liquid chromatography. The levels of eicosanoids studied in pregnant women differed not only according to the week of pregnancy but also in relation to individual anthropometric and biochemical parameters. Results: There was a significant correlation between being overweight and having a high BMI before pregnancy—as well as biochemical parameters of lipid and carbohydrate profiles—and the occurrence of pathological conditions in pregnancy. Conclusions: Eicosanoids are involved in the pathology of pregnancy associated with the occurrence of gestational diabetes and pre-eclampsia. Salicylic acid may find use in the treatment of pregnant women exposed to both phenomena, as well as in overweight and obese women found before pregnancy. Diets rich in natural salicylates, methods of administration, and pharmacotherapy and dosage need further study. Some of the mediators (lipoxin, prostaglandin and leucotrien) may be new diagnostic markers in pregnancy pathology and intervention pathways in the future. [ABSTRACT FROM AUTHOR]

Summary: Prostanoids and leukotrienes (LTs) are representative of ω6 fatty acid‐derived metabolites that exert their actions through specific receptors on the cell surface. These lipid mediators, being unstable in vivo, act locally at their production sites; thus, their physiological functions remain unclear. However, recent pharmacological and genetic approaches using experimental murine models have provided significant insights into the roles of these lipid mediators in various pathophysiological conditions, including cutaneous inflammatory diseases. These lipid mediators act not only through signaling by themselves but also by potentiating the signaling of other chemical mediators, such as cytokines and chemokines. For instance, prostaglandin E2‐EP4 and LTB4‐BLT1 signaling on cutaneous dendritic cells substantially facilitate their chemokine‐induced migration ability into the skin and play critical roles in the priming and/or activation of antigen‐specific effector T cells in the skin. In addition to these ω6 fatty acid‐derived metabolites, various ω3 fatty acid‐derived metabolites regulate skin immune cell functions, and some exert potent anti‐inflammatory functions. Lipid mediators act as modulators of cutaneous immune responses, and manipulating the signaling from lipid mediators has the potential as a novel therapeutic approach for human skin diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Breast cancer survivors face long-term sequelae compared to the general population, suggesting altered metabolic profiles after breast cancer. We used metabolomics approaches to investigate the metabolic differences between breast cancer patients and women in the general population, aiming to elaborate metabolic changes among breast cancer patients and identify potential targets for clinical interventions to mitigate long-term sequelae. Methods Serum samples were retrieved from 125 breast cancer cases recruited from the Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), and 125 healthy controls selected from Chicago Multiethnic Prevention and Surveillance Study (COMPASS). We used liquid chromatography-high resolution mass spectrometry to obtain untargeted metabolic profiles and partial least squares discriminant analysis (PLS-DA) combined with fold change to select metabolic features associated with breast cancer. Pathway analyses were conducted using Mummichog to identify differentially enriched metabolic pathways among cancer patients. As potential confounders we included age, marital status, tobacco smoking, alcohol drinking, type 2 diabetes, and area deprivation index in our model. Random effects of residence for intercept was also included in the model. We further conducted subgroup analysis by treatment timing (chemotherapy/radiotherapy/surgery), lymph node status, and cancer stages. Results The entire study participants were African American. The average ages were 57.1 for cases and 58.0 for controls. We extracted 15,829 features in total, among which 507 features were eventually selected by our criteria. Pathway enrichment analysis of these 507 features identified three differentially enriched metabolic pathways related to prostaglandin, leukotriene, and glycerophospholipid. The three pathways demonstrated inconsistent patterns. Metabolic features in the prostaglandin and leukotriene pathways exhibited increased abundances among cancer patients. In contrast, metabolic intensity in the glycerolphospholipid pathway was deregulated among cancer patients. Subgroup analysis yielded consistent results. However, changes in these pathways were strengthened when only using cases with positive lymph nodes, and attenuated when only using cases with stage I disease. Conclusion Breast cancer in African American women is associated with increase in serum metabolites involved in prostaglandin and leukotriene pathways, but with decrease in serum metabolites in glycerolphospholipid pathway. Positive lymph nodes and advanced cancer stage may strengthen changes in these pathways.

Purpose: Arthrofibrosis is a common inflammatory complication of joint trauma and surgery. 5lipoxygenase (5-LO) is a key enzyme involved in inflammation. Inhibition of 5-LO has been shown to reduce inflammation in heart and lung models but has not been examined in a joint contracture model. Methods: Twenty-six rats underwent joint contracture. Six rats served as non-surgical controls. A 5-LO inhibitor, caffeic acid (CA), suspended in 10% ethanol was orally administered to 14 rats and ethanol without CA to the remaining 12 rats daily for 21 days. Leukotriene B4 (LTB4) levels were measured, both systemically and locally. 5-LO levels in the posterior capsule were quantified by measuring the ratio of the length of the posterior capsule demonstrating 5-LO immunostaining to the total length of the capsule. Results: Joint contracture was successfully achieved in all rats who underwent manipulation. Levels of 5- LO measured in the posterior capsule were significantly increased in the animals who underwent surgery (56%/44–64) compared to the non-surgical control animals (7%/4–9). LTB4 levels were found to be significantly lower in the non-surgical control animals (107.79 ± 34.08 pg/ml) compared to all surgical animals (157.6 ± 55.3 pg/ml). Conclusion: Surgical intervention resulted in increased 5-LO activity of the synovial surface of the posterior capsule and increased LTB4 levels in the patellar tendon—fat pad. Oral administration of the 5LO inhibitor, CA, was ineffective at reducing systemic and local LTB4 levels and preventing knee joint contracture. Inhibiting 5-LO activity may still be effective in preventing arthrofibrosis and warrants further investigation. [ABSTRACT FROM AUTHOR]

Allergic inflammation of the airways such as allergic asthma is a major health problem with growing incidence world-wide. One cardinal feature in severe type 2-dominated airway inflammation is the release of lipid mediators of the eicosanoid family that can either promote or dampen allergic inflammation. Macrophages are key producers of prostaglandins and leukotrienes which play diverse roles in allergic airway inflammation and thus require tight control. Using RNA- and ATAC-sequencing, liquid chromatography coupled to mass spectrometry (LC-MS/MS), enzyme immunoassays (EIA), gene expression analysis and in vivo models, we show that the aryl hydrocarbon receptor (AhR) contributes to this control via transcriptional regulation of lipid mediator synthesis enzymes in bone marrow-derived as well as in primary alveolar macrophages. In the absence or inhibition of AhR activity, multiple genes of both the prostaglandin and the leukotriene pathway were downregulated, resulting in lower synthesis of prostanoids, such as prostaglandin E2 (PGE2), and cysteinyl leukotrienes, e.g., Leukotriene C4 (LTC4). These AhR-dependent genes include PTGS1 encoding for the enzyme cyclooxygenase 1 (COX1) and ALOX5 encoding for the arachidonate 5-lipoxygenase (5-LO) both of which major upstream regulators of the prostanoid and leukotriene pathway, respectively. This regulation is independent of the activation stimulus and partially also detectable in unstimulated macrophages suggesting an important role of basal AhR activity for eicosanoid production in steady state macrophages. Lastly, we demonstrate that AhR deficiency in hematopoietic but not epithelial cells aggravates house dust mite induced allergic airway inflammation. These results suggest an essential role for AhR-dependent eicosanoid regulation in macrophages during homeostasis and inflammation. [ABSTRACT FROM AUTHOR]

12(S)-hydroxyheptadecatrienoic acid (12-HHT) is a bioactive fatty acid synthesized from arachidonic acid via the cyclooxygenase pathway and serves as an endogenous ligand for the low-affinity leukotriene B4 receptor 2 (BLT2). Although the 12-HHT/BLT2 axis contributes to the maintenance of epithelial homeostasis, 12-HHT metabolism under physiological conditions is unclear. In this study, 12-keto-heptadecatrienoic acid (12-KHT) and 10,11-dihydro-12-KHT (10,11dh-12-KHT) were detected as 12-HHT metabolites in the human megakaryocytic cell line MEG01s. We found that 12-KHT and 10,11dh-12-KHT are produced from 12-HHT by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin reductase 1 (PTGR1), key enzymes in the degradation of prostaglandins, respectively. The 15-PGDH inhibitor SW033291 completely suppressed the production of 12-KHT and 10,11dh-12-KHT in MEG01s cells, resulting in a 9-fold accumulation of 12-HHT. 12-KHT and 10,11dh-12-KHT were produced in mouse skin wounds, and the levels were significantly suppressed by SW033291. Surprisingly, the agonistic activities of 12-KHT and 10,11dh-12-KHT on BLT2 were comparable to that of 12-HHT. Taken together, 12-HHT is metabolized into 12-KHT by 15-PGDH, and then 10,11dh-12-KHT by PTGR1 without losing the agonistic activity. [ABSTRACT FROM AUTHOR]

Objective: Triple negative breast cancer (TNBC) has high relapse rates due to dysregulated inflammatory signaling pathways and significant changes in the tumor microenvironment, probably influencing the failure of several therapies. The Cysteinyl Leukotriene Receptor 1 (CYSLTR1), a leukotriene modulator of inflammation, has been shown to play an important role in cancer pathogenesis and survival but few studies have been reported on its role in breast cancer. Materials and Methods: The present work was conducted using publicly available platforms that have omics data to assess the clinical potential of CYSLTR1 expression and its prognostic validation in large cohorts of samples from breast cancer patients. Web platforms containing clinical information, RNA-seq and protein data were selected to perform in silico analyses of the potential marker CYLSTR1. Added together, the platforms included modules for correlation, expression, prognosis, drug interactions, and construction of gene networks. Results: Kaplan–Meier curves revealed that reduced levels of CYSLTR1 corresponded to an unfavorable outcome for overall survival (p<0.005) as well as relapse-free survival (p<0.001) in the basal subtype. Additionally, CYSLTR1 was downregulated in breast tumor samples compared to adjacent healthy tissue (p<0.01) and the basal subtype exhibited the lowest expression of CYSLTR1 relative to the other subtypes (p<0.0001). Furthermore, gene networking analysis showed strong associations of CYSLTR1 with two protein-coding genes (P2RY10 and XCR1) when tested on a TNBC dataset. Conclusion: Our data highlighted the relevance of CYSLTR1 since it may play an important role in TNBC therapy. However, further in vitro and in vivo studies should be directed towards validating our findings in an effort to improve our understanding of TNBC pathology. [ABSTRACT FROM AUTHOR]

Allergic rhinitis as common airway disease has high prevalence in all peoples worldwide. In allergic diseases, Th2 cells release type 2 cytokines that support the inflammation in airways. All the drugs used for allergic rhinitis do not cure completely, and the choice of drugs according to cost and efficacy is very important in all groups of atopic patients. Therefore, in this study, the effect of commercial drugs on cytokine gene expression has been studied. Male Balb/c mice were divided into six groups. Allergic rhinitis was induced in five of the six groups with ovalbumin, and four of these five groups were treated with salbutamol, budesonide, theophylline, and montelukast. The fifth group was used as positive control group and the sixth group as negative control group. For the survey, RNA was extracted, cDNA was synthesized, and quantitative real‐time PCR was done for 21 genes. The four drugs had different effects on mRNA expression of cytokines (IL‐1b, 2, 4, 5, 7, 8, 9, 11, 12, 13, 17, 18, 22, 25, 31, 33, 37, IFN‐γ, TNF‐α, TGF‐β1, and eotaxin) in the allergic rhinitis groups. Salbutamol can be used during pregnancy and breastfeeding, but it has some side effects. Budesonide in the inhaled form is generally safe in pregnancy. Theophylline cannot control allergic attack in the long run. Montelukast is not useful in the treatment of acute allergic attacks. Immunomodulatory and anti‐inflammatory effects of drugs in control of allergic rhinitis via Th2 cytokines can be new approaches in molecular medicine. [ABSTRACT FROM AUTHOR]

Background: In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR-Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR-Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence-based findings and recommendation fromthe full document. Methods: ICAR-Allergic Rhinitis 2023 employed established evidence-based reviewwith recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensuswas performed for each topic. The final document was then collated and includes the results of this work. Results: ICAR-Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost. Conclusion: The ICAR-Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment. [ABSTRACT FROM AUTHOR]

Background: Montelukast (MTK), a potent antagonist of cysteinyl leukotriene receptor 1, has shown therapeutic promise for the treatment of neuropsychiatric disorders. Delirium, a common complication in critically ill patients, lacks effective treatment. This study aims to explore the impact of pre-intensive care unit (ICU) MTK use on in-hospital delirium incidence and, subsequent, prognosis in critically ill patients. Methods: A retrospective cohort study (n = 6344) was conducted using the MIMIC-IV database. After propensity score matching, logistic/Cox regression, E-value sensitivity analysis, and causal mediation analysis were performed to assess associations between pre-ICU MTK exposure and delirium and prognosis in critically ill patients. Results: Pre-ICU MTK use was significantly associated with reduced in-hospital delirium (OR: 0.705; 95% CI 0.497–0.999; p = 0.049) and 90-day mortality (OR: 0.554; 95% CI 0.366–0.840; p = 0.005). The association was more significant in patients without myocardial infarction (OR: 0.856; 95% CI 0.383–0.896; p = 0.014) and could be increased by extending the duration of use. Causal mediation analysis showed that the reduction in delirium partially mediated the association between MTK and 90-day mortality (ACME: −0.053; 95% CI −0.0142 to 0.0002; p = 0.020). Conclusions: In critically ill patients, MTK has shown promising therapeutic benefits by reducing the incidence of delirium and 90-day mortality. This study highlights the potential of MTK, beyond its traditional use in respiratory disease, and may contribute to the development of novel therapeutic strategies for delirium.

Allergic inflammation of the airways such as allergic asthma is a major health problem with growing incidence world-wide. One cardinal feature in severe type 2-dominated airway inflammation is the release of lipid mediators of the eicosanoid family that can either promote or dampen allergic inflammation. Macrophages are key producers of prostaglandins and leukotrienes which play diverse roles in allergic airway inflammation and thus require tight control. Using RNA- and ATAC-sequencing, liquid chromatography coupled to mass spectrometry (LC-MS/MS), enzyme immunoassays (EIA), gene expression analysis and in vivo models, we show that the aryl hydrocarbon receptor (AhR) contributes to this control via transcriptional regulation of lipid mediator synthesis enzymes in bone marrow-derived as well as in primary alveolar macrophages. In the absence or inhibition of AhR activity, multiple genes of both the prostaglandin and the leukotriene pathway were downregulated, resulting in lower synthesis of prostanoids, such as prostaglandin E2 (PGE2), and cysteinyl leukotrienes, e.g., Leukotriene C4 (LTC4). These AhR-dependent genes include PTGS1 encoding for the enzyme cyclooxygenase 1 (COX1) and ALOX5 encoding for the arachidonate 5-lipoxygenase (5-LO) both of which major upstream regulators of the prostanoid and leukotriene pathway, respectively. This regulation is independent of the activation stimulus and partially also detectable in unstimulated macrophages suggesting an important role of basal AhR activity for eicosanoid production in steady state macrophages. Lastly, we demonstrate that AhR deficiency in hematopoietic but not epithelial cells aggravates house dust mite induced allergic airway inflammation. These results suggest an essential role for AhR-dependent eicosanoid regulation in macrophages during homeostasis and inflammation.

Gastric injury is mainly described by inflammation of the gastric epithelium. Recently, our group of work demonstrated that Prosthechea karwinskii leaves extract induces both an in vitro antioxidative action and an in vivo gastroprotective effect in a rat. However, the molecules involved in the gastroprotective action by Prosthechea karwinskii are not known. Thus, the aim of this study is to determine whether Prosthechea karwinskii extract modifies anti-inflammatory and antioxidative biomarkers in an in vivo rat model of indomethacin-induced gastric injury. Rats were orally administered with indomethacin and Prosthechea karwinskii leaf extract. Our results suggest that the gastroprotective effect of Prosthechea karwinskii leaf extract is related to the reduction in leukocyte infiltration and antioxidative action in a model of indomethacin-induced gastric injury. Further studies are warranted to investigate the role of the compounds identified in the gastroprotective action of Prosthechea karwinskii leaves extract. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma multiforme is a brain tumor with a very unfavorable prognosis, where the vast majority of patients do not survive a year after diagnosis. One line of research that may help in designing more successful therapeutic approaches is the synthesis and metabolism of arachidonic acid, which is then converted into a large number of different lipid mediators, including prostaglandins and leukotrienes (by cyclooxygenases and lipoxygenases, respectively). In this paper, we discuss the synthesis of arachidonic acid in glioblastoma multiforme tumors as well as the significance of lipid mediators synthesized from arachidonic acid, which can increase the proliferation of glioblastoma multiforme cancer cells, cause angiogenesis, inhibit the anti-tumor response of the immune system, and be responsible for resistance to treatment. Glioblastoma multiforme (GBM) is one of the most aggressive gliomas. New and more effective therapeutic approaches are being sought based on studies of the various mechanisms of GBM tumorigenesis, including the synthesis and metabolism of arachidonic acid (ARA), an omega-6 polyunsaturated fatty acid (PUFA). PubMed, GEPIA, and the transcriptomics analysis carried out by Seifert et al. were used in writing this paper. In this paper, we discuss in detail the biosynthesis of this acid in GBM tumors, with a special focus on certain enzymes: fatty acid desaturase (FADS)1, FADS2, and elongation of long-chain fatty acids family member 5 (ELOVL5). We also discuss ARA metabolism, particularly its release from cell membrane phospholipids by phospholipase A2 (cPLA2, iPLA2, and sPLA2) and its processing by cyclooxygenases (COX-1 and COX-2), lipoxygenases (5-LOX, 12-LOX, 15-LOX-1, and 15-LOX-2), and cytochrome P450. Next, we discuss the significance of lipid mediators synthesized from ARA in GBM cancer processes, including prostaglandins (PGE2, PGD2, and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2)), thromboxane A2 (TxA2), oxo-eicosatetraenoic acids, leukotrienes (LTB4, LTC4, LTD4, and LTE4), lipoxins, and many others. These lipid mediators can increase the proliferation of GBM cancer cells, cause angiogenesis, inhibit the anti-tumor response of the immune system, and be responsible for resistance to treatment. [ABSTRACT FROM AUTHOR]

Aspirin-exacerbated respiratory disease (AERD) is associated with overproduction of proinflammatory cysteinyl leukotrienes (CysLTs), defective generation of anti-inflammatory prostaglandin E 2 (PGE 2), and reduced expression of the EP2 receptor for PGE 2. Reduced PGE 2 synthesis results from the downregulation of inducible COX-2. Because PGE 2 signaling via EP2 inhibits the 5-lipoxygenase/leukotriene C 4 synthase–dependent pathway, the deficient levels of both PGE 2 and EP2 likely contribute to the excessive baseline production of cysteinyl leukotrienes in patients with AERD compared with in patients with aspirin-tolerant asthma. The COX-2 pathway is regulated by an autocrine metabolic loop involving IL-1β, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE 2 prostaglandin E 2 synthase-1, and PGE 2. Previous studies reported that this metabolic loop is dysregulated in patients with AERD. When the downexpressed EP2 receptor is normalized, the entire loop returns to its normal function. Cotreatment of airway cells from healthy subjects with IL-4 and IFN-γ induces alterations in the metabolic loop similar to those seen in patients with AERD. In these patients, IL-4, which is produced in excess in airways of patients with AERD, likely contributes to the alteration of normal functioning of the autocrine metabolic loop involving IL-1β, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE 2 prostaglandin E 2 synthase-1, and PGE 2. We hypothesized that by blocking IL-4 action, dupilumab normalizes EP2 expression and restores the normal functioning of the COX-2 pathway autocrine metabolic loop, thereby normalizing the synthesis of PGE 2 and restoring aspirin tolerance. [ABSTRACT FROM AUTHOR]

Leukotrienes are potent immune-regulating lipid mediators with patho-genic roles in inflammatory and allergic diseases, particularly asthma. These autacoids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, metabolic, and tumor diseases. Biosynthesis of leukotrienes involves release and oxidative metabolism of arachidonic acid and proceeds via a set of cytosolic and integral membrane enzymes that are typically expressed by cells of the innate immune system. In activated cells, these enzymes traffic and assemble at the endoplasmic and perinuclear membrane, together comprising a biosynthetic complex. Here we describe recent advances in our molecular understanding of the protein components of the leukotriene-synthesizing enzyme machinery and also briefly touch upon the leukotriene receptors. Moreover, we discuss emerging opportunities for pharmacological intervention and development of new therapeutics. [ABSTRACT FROM AUTHOR]

This mini-review addresses lipoxygenases and receptors for leukotrienes in hematological malignancies. Potential novel biomarkers and drug targets in leukemia and B-cell lymphoma are discussed. • B-cell chronic lymphocytic leukemia and B-cell lymphoma have high expression of 5-lipoxygenase. • Inhibition of the 5-lipoxygenase pathway or leukotriene B 4 receptor might inhibit the migration of malignant B cells. • Chronic myeloid leukemia cells possess high leukotriene C 4 synthase activity. • Hodgkin Reed-Sternberg cells express 15-lipoxygenase and cysteinyl-leukotriene receptor 1. • Potential novel biomarkers and drug targets in hematological malignancies are discussed. [ABSTRACT FROM AUTHOR]

Abstract Background Leukotriene B4 (LTB4) is a potent lipid mediator that stimulate the immune response. Because dental pulp inflammation and dentin repair are intrinsically related responses, the aim of this research was to investigate the potential of LTB4 in inducing differentiation of dental pulp stem cells. Methods Microspheres (MS) loaded with LTB4 were prepared using an oil emulsion solvent extraction evaporation process and sterility, characterization, efficiency of LTB4 encapsulation and in vitro LTB4 release assay were investigated. Mouse dental pulp stem cells (OD-21) were stimulated with soluble LTB4 or MS loaded with LTB4 (0.01 and 0.1 μM). Cytotoxicity and cell viability was determined by lactate dehydrogenase and methylthiazol tetrazolium assays. Gene expression were measured by quantitative reverse transcription polymerase chain reaction after 3, 6, 24, 48 and 72 h. Mineralized nodule formation was assessed after 28 days of OD-21 cell stimulation with LTB4 in mineralized media or not. Groups were compared using one-way ANOVA test followed by Dunnett’s post-test (α = 0.05). Results Treatment with LTB4 or MS loaded with LTB4 (0.01 and 0.1 µm-μM) were not cytotoxic to OD-21 cells. Treatment with LTB4 modulated the expression of the Ibsp (integrin binding sialoprotein) and Runx2 (runt-related transcription factor 2) genes differently depending on the experimental period analyzed. Interestingly LTB4 loaded in microspheres (0.1 μM) allowed long term dental pulp cell differentiation and biomineralization. Conclusion LTB4, soluble or loaded in MS, were not cytotoxic and modulated the expression of the Ibsp and Runx2 genes in cultured OD-21 cells. When LTB4 was incorporated into MS, odontoblast differentiation and mineralization was induced in long term culture.

Abstract Purpose Arthrofibrosis is a common inflammatory complication of joint trauma and surgery. 5lipoxygenase (5‐LO) is a key enzyme involved in inflammation. Inhibition of 5‐LO has been shown to reduce inflammation in heart and lung models but has not been examined in a joint contracture model. Methods Twenty‐six rats underwent joint contracture. Six rats served as non‐surgical controls. A 5‐LO inhibitor, caffeic acid (CA), suspended in 10% ethanol was orally administered to 14 rats and ethanol without CA to the remaining 12 rats daily for 21 days. Leukotriene B4 (LTB4) levels were measured, both systemically and locally. 5‐LO levels in the posterior capsule were quantified by measuring the ratio of the length of the posterior capsule demonstrating 5‐LO immunostaining to the total length of the capsule. Results Joint contracture was successfully achieved in all rats who underwent manipulation. Levels of 5‐ LO measured in the posterior capsule were significantly increased in the animals who underwent surgery (56%/44–64) compared to the non‐surgical control animals (7%/4–9). LTB4 levels were found to be significantly lower in the non‐surgical control animals (107.79 ± 34.08 pg/ml) compared to all surgical animals (157.6 ± 55.3 pg/ml). Conclusion Surgical intervention resulted in increased 5‐LO activity of the synovial surface of the posterior capsule and increased LTB4 levels in the patellar tendon—fat pad. Oral administration of the 5LO inhibitor, CA, was ineffective at reducing systemic and local LTB4 levels and preventing knee joint contracture. Inhibiting 5‐LO activity may still be effective in preventing arthrofibrosis and warrants further investigation.

Background: Antihistamines (ATH) and intranasal corticosteroids (INCS) are primary treatments for patients with allergic rhinitis (AR). When monotherapy of either primary treatment fails to control symptoms, combined medical therapy is an option. In this meta‐analysis we assessed the additional effects of different medical combinations compared with primary treatments. Methods: Systematic searches on PubMed and EMBASE were updated on November 4, 2021. Randomized, controlled trials comparing the effects of combinations with monotherapy were included. There were 7 comparisons: (1) ATH‐decongestant vs ATH; (2) ATH‐leukotriene receptor antagonist (LTRA) vs ATH; (3) INCS‐ATH vs INCS; (4) INCS‐LTRA vs INCS; (5) INCS‐decongestion vs INCS; (6) INCS‐saline irrigation vs INCS; and (7) ATH‐saline irrigation vs ATH. Data were pooled for meta‐analysis. Outcomes were composite nasal symptom score, composite ocular symptom score, quality of life (QoL), and adverse events. Results: Fifty‐three studies were included. Compared with ATH alone, the ATH‐decongestant combination improved composite nasal symptoms; ATH‐LTRA improved nasal symptoms in patients with perennial AR; and ATH‐nasal saline improved both symptoms and QoL. Compared with INCS alone, the INCS‐intranasal ATH combination improved nasal symptoms, ocular symptoms, and QoL; INCS‐LTRA improved ocular symptoms but not nasal symptoms; and INCS‐nasal saline improved QoL but not symptoms. There were no additional effects observed from adding oral ATH or topical decongestant to INCS. Conclusion: After ATH monotherapy fails to control symptoms, addition of decongestant, saline, or LTRA can improve the outcomes. When INCS monotherapy is ineffective, addition of intranasal ATH can improve nasal symptoms; LTRA can improve ocular symptoms, and saline irrigation can improve QoL. [ABSTRACT FROM AUTHOR]

Leukotrienes are pro-inflammatory vasoactive lipid mediators implicated in the pathophysiology of atherosclerotic cardiovascular disease. We studied the effect of the 5-lipoxygenase-activating protein inhibitor AZD5718 on leukotriene biosynthesis and coronary microvascular function in a single-blind, phase 2a study. Patients 7–28 days after myocardial infarction (±ST elevation), with <50% left anterior descending coronary artery stenosis and Thrombolysis in Myocardial Infarction flow grade ≥ 2 after percutaneous coronary intervention, were randomized 2:1:2 to once-daily AZD5718 200 mg or 50 mg, or placebo, in 4- and 12-week cohorts. Change in urine leukotriene E 4 (uLTE 4) was the primary endpoint, and coronary flow velocity reserve (CFVR; via echocardiography) was the key secondary endpoint. Of 129 randomized patients, 128 received treatment (200 mg, n = 52; 50 mg, n = 25; placebo, n = 51). Statistically significant reductions in uLTE 4 levels of >80% were observed in both AZD5718 groups versus the placebo group at 4 and 12 weeks. No significant changes in CFVR were observed for AZD5718 versus placebo. Adverse events (AEs) occurred in 12/18, 3/6 and 6/13 patients receiving 200 mg, 50 mg and placebo, respectively, in the 4-week cohort, and in 27/34, 14/19 and 24/38 patients, respectively, in the 12-week cohort. Serious AEs in seven patients receiving AZD5718 and four receiving placebo were not treatment-related, and there were no deaths. In patients with recent myocardial infarction, AZD5718 was well tolerated, and leukotriene biosynthesis was dose-dependently inhibited. No significant changes in CFVR were detected. ClinicalTrials.gov identifier: NCT03317002. [Display omitted] • Leukotrienes are implicated in the pathophysiology of atherosclerotic CV disease. • AZD5718 is a 5-lipoxygenase-activating protein inhibitor. • In patients with recent myocardial infarction, AZD5718 was well tolerated. • AZD5718 significantly reduced leukotriene E 4 levels compared with placebo. [ABSTRACT FROM AUTHOR]

Acute coronary syndrome (ACS) is a set of signs and symptoms caused by a reduction of coronary blood flow with subsequent myocardial ischemia. ACS is associated with activation of the leukotriene (LT) pathway with subsequent releases of various LTs, including LTB4, LTC4, and LTD4, which cause inflammatory changes and induction of immunothrombosis. LTs through cysteine leukotriene (CysLT) induce activation of platelets and clotting factors with succeeding coronary thrombosis. CysLT receptor (CysLTR) antagonists such as montelukast (MK) may reduce the risk of the development of ACS and associated complications through suppression of the activation of platelet and clotting factors. Thus, this critical review aimed to elucidate the possible protective role of MK in the management of ACS. The LT pathway is implicated in the pathogenesis of atherosclerosis, cardiac hypertrophy, and heart failure. Inhibition of the LT pathway and CysL1TR by MK might be effective in preventing cardiovascular complications. MK could be an effective novel therapy in the management of ACS through inhibition of pro-inflammatory CysLT1R and modulation of inflammatory signaling pathways. MK can attenuate thrombotic events by inhibiting platelet activation and clotting factors that are activated during the development of ACS. In conclusion, MK could be an effective agent in reducing the severity of ACS and associated complications. Experimental, preclinical, and clinical studies are recommended to confirm the potential therapeutic of MK in the management of ACS. [ABSTRACT FROM AUTHOR]

Background: This paper discusses the role of inflammation in the pathogenesis of nondipping blood pressure and its role in the pathogenesis of obstructive sleep apnea syndrome. The aim of the study was to assess the impact of free fatty acids (FAs) and their inflammatory metabolites on the nondipping phenomenon and the risk of sleep apnea in stroke patients. Methods: Sixty-four ischemic stroke patients were included in the prospective study. Group I consisted of 33 patients with a preserved physiological dipping effect (DIP), while group II included 31 patients with the nondipping phenomenon (NDIP). All subjects had FA gas chromatography and inflammatory metabolite measurements performed with the use of liquid chromatography, their 24 h blood pressure was recorded, and they were assessed with the Epworth sleepiness scale (ESS). Results: In the nondipping group a higher level of C16:0 palmitic acid was observed, while lower levels were observed in regard to C20:0 arachidic acid, C22:0 behenic acid and C24:1 nervonic acid. A decreased leukotriene B4 level was recorded in the nondipping group. None of the FAs and derivatives correlated with the ESS scale in the group of patients after stroke. Correlations were observed after dividing into the DIP and NDIP groups. In the DIP group, a higher score of ESS was correlated with numerous FAs and derivatives. Inflammation of a lower degree and a higher level of anti-inflammatory mediators from EPA and DHA acids favored the occurrence of the DIP. A high level of C18: 3n6 gamma linoleic acid indicating advanced inflammation, intensified the NDIP effect. Conclusions: We demonstrated potential novel associations between the FA levels and eicosanoids in the pathogenesis of the nondipping phenomenon. There are common connections between fatty acids, their metabolites, inflammation, obstructive sleep apnea syndrome and nondipping in stroke patients. [ABSTRACT FROM AUTHOR]

Acute inflammation caused by bacterial infections is an essential biological defence mechanism of the host in order to neutralize and clear the invaders and to return to homeostasis. Despite its protective function, inflammation may become persistent and uncontrolled, resulting in chronic diseases and tissue destruction as consequence of the unresolved inflammatory process. Therefore, spatiotemporal induction of endogenous inflammation resolution programs that govern bacterial clearance as well as tissue repair and regeneration, are of major importance in order to enable tissues to restore functions. Lipid mediators that are de‐novo biosynthesized from polyunsaturated fatty acids (PUFAs) mainly by lipoxygenases and cyclooxygenases, critically regulate the initiation, the maintenance but also the resolution of infectious inflammation and tissue regeneration. The discovery of specialized pro‐resolving mediators (SPMs) generated from omega‐3 PUFAs stimulated intensive research in inflammation resolution, especially in infectious inflammation elicited by bacteria. SPMs are immunoresolvents that actively terminate inflammation by limiting neutrophil influx, stimulating phagocytosis, bacterial killing and clearance as well as efferocytosis of apoptotic neutrophils and cellular debris by macrophages. Moreover, SPMs prevent collateral tissue damage, promote tissue repair and regeneration and lower antibiotic requirement. Here, we review the biosynthesis of SPMs in bacterial infections and cover specific mechanisms of SPMs that govern the resolution of bacteria‐initiated inflammation. [ABSTRACT FROM AUTHOR]

Abstract Purpose To evaluate the safety and preliminary efficacy of topical rVA576, a dual inhibitor of complement component 5 (C5) and leukotriene B4 (LTB4), in patients with recalcitrant atopic keratoconjunctivitis (AKC) in the open label phase 1 TRACKER clinical trial. Methods Three patients diagnosed with moderate or severe AKC who had been on maximal topical treatment (antihistamines and ciclosporin) for at least three months prior to entry, and showed persistent symptoms and signs of inflammation, were recruited into the trial. Patients received rVA576 eye drops twice a day for 8 weeks. Patients were seen at baseline and weeks 1, 2, 4, 6 and 8. Safety data was recorded and a composite sum score of symptoms and signs was obtained. This score comprised symptoms such as itching, mucous discharge and photophobia, and conjunctival and corneal signs such as hyperemia, tarsal papillae, punctate keratitis and corneal neovascularization, all rated individually from 0 to 3 for a maximum score of 33. Results Two of the three patients completed the initial open label phase of the trial. The third patient was unable to attend appointments and terminated the study early at day 14. Topical rVA576 was well tolerated with no serious adverse events reported. There was an average improvement in overall clinical score of 53%, composed of an improvement in symptoms of 65% [63.64–66.67%] and signs of 40% [40–40.12%] by day 56. Conclusions In this open label phase 1 TRACKER trial, rVA576 eye drops were well tolerated and showed a response across signs and symptoms of active inflammation. This study is exploratory but supports topical rVA576 safety and shows promising efficacy for recalcitrant AKC. A phase 2 randomised control trial is currently underway.

Simple Summary: Aspirin and related drugs with anti-inflammatory effects have lung cancer prevention effects in laboratory studies and through their use in populations at risk for lung cancer. We studied aspirin plus zileuton compared to two placebo pills for 3 months in smokers. We studied genes associated with lung cancer, smoking, and lung disease. We used nasal swabs to collect nasal cells that were smoke exposed to look for changes in these genes. We found that most of the gene panels in the nasal cells related to smoking and lung cancer lung disease did not change in a favorable way, but we did see a favorable change in a gene panel representing abnormal squamous cells that may progress to lung cancer. We think this finding is of interest and can be studied further using deep lung biopsies to understand if this drug effect occurs where squamous cell lung cancer actually starts. The chemopreventive effect of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on lung cancer risk is supported by epidemiologic and preclinical studies. Zileuton, a 5-lipoxygenase inhibitor, has additive activity with NSAIDs against tobacco carcinogenesis in preclinical models. We hypothesized that cyclooxygenase plus 5-lipoxygenase inhibition would be more effective than a placebo in modulating the nasal epithelium gene signatures of tobacco exposure and lung cancer. We conducted a randomized, double-blinded study of low-dose aspirin plus zileuton vs. double placebo in current smokers to compare the modulating effects on nasal gene expression and arachidonic acid metabolism. In total, 63 participants took aspirin 81 mg daily plus zileuton (Zyflo CR) 600 mg BID or the placebo for 12 weeks. Nasal brushes from the baseline, end-of-intervention, and one-week post intervention were profiled via microarray. Aspirin plus zilueton had minimal effects on the modulation of the nasal or bronchial gene expression signatures of smoking, lung cancer, and COPD but favorably modulated a bronchial gene expression signature of squamous dysplasia. Aspirin plus zileuton suppressed urinary leukotriene but not prostaglandin E2, suggesting shunting through the cyclooxygenase pathway when combined with 5-lipoxygenase inhibition. Continued investigation of leukotriene inhibitors is needed to confirm these findings, understand the long-term effects on the airway epithelium, and identify the safest, optimally dosed agents. [ABSTRACT FROM AUTHOR]

Several therapeutic agents have been assessed for the treatment of COVID-19, but few approaches have been proven efficacious. Because leukotriene receptor antagonists, such as montelukast have been shown to reduce both cytokine release and lung inflammation in preclinical models of viral influenza and acute respiratory distress syndrome, we hypothesized that therapy with montelukast could be used to treat COVID-19. The objective of this study was to determine if montelukast treatment would reduce the rate of clinical deterioration as measured by the COVID-19 Ordinal Scale. We performed a retrospective analysis of COVID-19 confirmed hospitalized patients treated with or without montelukast. We used "clinical deterioration" as the primary endpoint, a binary outcome defined as any increase in the Ordinal Scale value from Day 1 to Day 3 of the hospital stay, as these data were uniformly available for all admitted patients before hospital discharge. Rates of clinical deterioration between the montelukast and non-montelukast groups were compared using the Fisher's exact test. Univariate logistic regression was also used to assess the association between montelukast use and clinical deterioration. A total of 92 patients were analyzed, 30 who received montelukast at the discretion of the treating physician and 62 patients who did not receive montelukast. Patients receiving montelukast experienced significantly fewer events of clinical deterioration compared with patients not receiving montelukast (10% vs 32%, p = 0.022). Our findings suggest that montelukast associates with a reduction in clinical deterioration for COVID-19 confirmed patients as measured on the COVID-19 Ordinal Scale. Hospitalized COVID-19 patients treated with montelukast had fewer events of clinical deterioration, indicating that this treatment may have clinical activity. While this retrospective study highlights a potential pathway for COVID-19 treatment, this hypothesis requires further study by prospective studies. [ABSTRACT FROM AUTHOR]

Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of oxidation of polyenoic fatty acids such as arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. One hallmark of SPM formation is that reported levels of these lipid mediators are much lower than typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g., 5-HETE), leukotrienes or certain cyclooxygenase-derived prostaglandins. Thus, reliable detection and quantification of these metabolites is challenging. This paper is aimed at critically evaluating i) the proposed biosynthetic pathways of SPM formation, ii) the current knowledge on SPM receptors and their signaling cascades and iii) the analytical methods used to quantify these pro-resolving mediators in the context of their instability and their low concentrations. Based on current literature it can be concluded that i) there is at most, a low biosynthetic capacity for SPMs in human leukocytes. ii) The identity and the signaling of the proposed G-protein-coupled SPM receptors have not been supported by studies in knock-out mice and remain to be validated. iii) In humans, SPM levels were neither related to dietary supplementation with their ω-3 polyunsaturated fatty acid precursors nor were they formed during the resolution phase of an evoked inflammatory response. iv) The reported low SPM levels cannot be reliably quantified by means of the most commonly reported methodology. Overall, these questions regarding formation, signaling and occurrence of SPMs challenge their role as endogenous mediators of the resolution of inflammation. [ABSTRACT FROM AUTHOR]

Background: Leukotriene B4 (LTB4) is a potent lipid mediator that stimulate the immune response. Because dental pulp inflammation and dentin repair are intrinsically related responses, the aim of this research was to investigate the potential of LTB4 in inducing differentiation of dental pulp stem cells. Methods: Microspheres (MS) loaded with LTB4 were prepared using an oil emulsion solvent extraction evaporation process and sterility, characterization, efficiency of LTB4 encapsulation and in vitro LTB4 release assay were investigated. Mouse dental pulp stem cells (OD-21) were stimulated with soluble LTB4 or MS loaded with LTB4 (0.01 and 0.1 μM). Cytotoxicity and cell viability was determined by lactate dehydrogenase and methylthiazol tetrazolium assays. Gene expression were measured by quantitative reverse transcription polymerase chain reaction after 3, 6, 24, 48 and 72 h. Mineralized nodule formation was assessed after 28 days of OD-21 cell stimulation with LTB4 in mineralized media or not. Groups were compared using one-way ANOVA test followed by Dunnett's post-test (α = 0.05). Results: Treatment with LTB4 or MS loaded with LTB4 (0.01 and 0.1 µm-μM) were not cytotoxic to OD-21 cells. Treatment with LTB4 modulated the expression of the Ibsp (integrin binding sialoprotein) and Runx2 (runt-related transcription factor 2) genes differently depending on the experimental period analyzed. Interestingly LTB4 loaded in microspheres (0.1 μM) allowed long term dental pulp cell differentiation and biomineralization. Conclusion: LTB4, soluble or loaded in MS, were not cytotoxic and modulated the expression of the Ibsp and Runx2 genes in cultured OD-21 cells. When LTB4 was incorporated into MS, odontoblast differentiation and mineralization was induced in long term culture. [ABSTRACT FROM AUTHOR]

Abstract A significant role in the pathogenesis of rhinosinusitis is played by an inflammatory reaction in the maxillary sinuses of the nasal cavity. Leukotrienes are the most powerful mediators of inflammation, especially at the early stages. The effect of combined dry extract BNO 1016 could be useful for the inhibition of the inflammation in rhinosinusitis. Thus, it appears reasonable to study the anti-inflammatory activity of the combined dry extract BNO 1016. Materials and methods The tested drug is the combined dry extract BNO 1016 produced by “Bionorica SE”. The reference drug is Ibuprofen. Leukotriene inflammation was induced by subplantar injection of zymozan into the right hind paw of male and female Wistar rats. Volumes of the resulting edema were measured and levels of anti-inflammatory activity together with mean effective dose (ED50) were calculated. Results The highest anti-inflammatory activity was observed at a dose level of 500 mg/kg of BNO 1016 during all time-points of the experiment and reached 65.2% 2 h after induction of inflammation. The anti-inflammatory activity of BNO 1016 at 500 mg/kg was credibly higher than that of Ibuprofen at all time-points of the experiment. Based on the data obtained from this leukotriene-dependent inflammation experiment the mean effective dose (ED50) for anti-inflammatory activity of dry combined extract BNO 1016 was calculated with help of Probit analysis. Conclusion The combined dry extract BNO 1016 shows a high level of anti-inflammatory activity in leukotriene-dependent inflammation which is very promising for the improvement of the treatment of patients. However, additional preclinical and clinical research on this drug should be carried out.

Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of oxidation of polyenoic fatty acids such as arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. One hallmark of SPM formation is that reported levels of these lipid mediators are much lower than typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g., 5-HETE), leukotrienes or certain cyclooxygenase-derived prostaglandins. Thus, reliable detection and quantification of these metabolites is challenging. This paper is aimed at critically evaluating i) the proposed biosynthetic pathways of SPM formation, ii) the current knowledge on SPM receptors and their signaling cascades and iii) the analytical methods used to quantify these pro-resolving mediators in the context of their instability and their low concentrations. Based on current literature it can be concluded that i) there is at most, a low biosynthetic capacity for SPMs in human leukocytes. ii) The identity and the signaling of the proposed G-protein-coupled SPM receptors have not been supported by studies in knock-out mice and remain to be validated. iii) In humans, SPM levels were neither related to dietary supplementation with their ω-3 polyunsaturated fatty acid precursors nor were they formed during the resolution phase of an evoked inflammatory response. iv) The reported low SPM levels cannot be reliably quantified by means of the most commonly reported methodology. Overall, these questions regarding formation, signaling and occurrence of SPMs challenge their role as endogenous mediators of the resolution of inflammation.

This study aimed to evaluate the levels of eicosanoids derived from arachidonic acid (ARA) in the lungs of asthmatic rats supplemented with fish oil. The present data gives insight into the action of fish oil in asthma, related to its inability to modify the contractile capacity of tracheal smooth muscle reported previously in a model of asthma in rats. Male Wistar rats were supplemented daily with 1 g of fish oil/kg of body weight for 21 days. They were exposed to ovalbumin (OVA) after previous sensitization with OVA to induce asthma. Pulmonary levels of five eicosanoids were measured using immunoassay kits: PGE2, TXB2, LTB4, LXA4, and 8-iso PGF2α. In asthmatic rats, supplementation with fish oil resulted in lower concentrations of lung eicosanoids produced by cyclooxygenase-2 and 15-lipoxygenase: PGE2, TXB2, and LXA4, respectively. Fish oil supplementation also decreased the non-enzymatically produced eicosanoid 8-iso PGF2α. Fish oil supplementation did not affect LTB4, a metabolite of 5-lipoxygenase. The limited efficacy of fish oil supplementation in asthmatic rats is associated with a lack of action in reducing the levels of LTB4 in the lungs. Thus, fish oil differentially modulates the concentrations of eicosanoids derived from ARA via specific pathways in an animal model of asthma.

Eosinophilic asthma and nasal polyposis are hallmarks of aspirin-exacerbated respiratory disease (AERD), and IL-5 inhibition has been shown to provide therapeutic benefit. However, IL-5Rα is expressed on many cells in addition to eosinophils, and the mechanisms by which IL-5 inhibition leads to clinical benefit in eosinophilic asthma and nasal polyposis are unlikely to be due exclusively to antieosinophil effects. We sought to identify the mechanisms by which anti–IL-5 treatment with mepolizumab improves respiratory inflammation in AERD. The clinical characteristics, circulating granulocytes, nasal scraping transcripts, eosinophilic cationic protein, tryptase, and antibody levels, and urinary and nasal eicosanoid levels were measured for 18 subjects with AERD who were taking mepolizumab and compared with those of 18 matched subjects with AERD who were not taking mepolizumab. Subjects taking mepolizumab had significantly fewer peripheral blood eosinophils and basophils, and those cells that remained had higher surface CRTH2 expression than did the cells from subjects not taking mepolizumab. Nasal prostaglandin F 2α , prostaglandin D 2 metabolites, leukotriene B 4 , and thromboxane levels were lower in subjects taking mepolizumab, as were urinary levels of tetranor–prostaglandin D 2 and leukotriene E 4. The nasal epithelial cell transcripts that were overexpressed among subjects with AERD who were taking mepolizumab were enriched for genes involved in tight junction formation and cilium organization. Nasal and urinary prostaglandin E 2 , tryptase, and antibody levels were not different between the 2 groups. IL-5 inhibition in AERD decreases production of inflammatory eicosanoids and upregulates tight junction–associated nasal epithelial cell transcripts, likely due to decreased IL-5 signaling on tissue mast cells, eosinophils, and epithelial cells. These direct effects on multiple relevant immune cells contribute to the mechanism of benefit afforded by mepolizumab. [Display omitted] [ABSTRACT FROM AUTHOR]

A variety of novel indole-derived γ-hydroxy propiolate esters were designed, synthesized, and evaluated for their anti-inflammatory activity in-vitro and in-vivo. According to the nitric oxide (NO) inhibitory analysis, all compounds showed potent NO inhibitory ability in a dose-dependent manner, with no apparent cytotoxicity. The model compound, L-37, also exhibited significant potency in PGE 2 inhibition. In addition, compounds L-37 and L-39 can downregulate the expression of COX-2 enzyme at 5 μM via ELISA experiment. Compound L-37 (1 μM) also inhibited the PGF 1 production as well as the expression of COX-1, but displayed weak inhibition activity towards the Leukotrienes (LT) and Thromboxane-B2 (TXB-2) production. However, the expression of 5-LOX was significantly inhibited by compound L-39 at 5 μM. Xylene-induced ear edema model was explored for in-vivo anti-inflammatory evaluation, compound L-37 showed similar inhibitory activity compared with celecoxib, approximately 80% at 50 mg/kg dosage. Every outcome showed that the newly synthesized compounds can effectively inhibit inflammation. [Display omitted] • A series of indole-derived γ-hydroxy propiolate esters were designed and synthesized. • These indole-derived γ-hydroxy propiolate esters were highly potent, inhibiting LPS-induced nitric oxide release with no apparent cytotoxicity. • Model compounds L-37 and L-39 have significant potency on PGE 2 , COX-2, COX-1, and 5-LOX inhibition. • Compound L-37 displayed remarkable in-vivo anti-inflammatory activity via the xylene-induced mice ear edema model. [ABSTRACT FROM AUTHOR]

Background: This paper discusses the role of inflammation in the pathogenesis of nondipping blood pressure and its role in the pathogenesis of obstructive sleep apnea syndrome. The aim of the study was to assess the impact of free fatty acids (FAs) and their inflammatory metabolites on the nondipping phenomenon and the risk of sleep apnea in stroke patients. Methods: Sixty-four ischemic stroke patients were included in the prospective study. Group I consisted of 33 patients with a preserved physiological dipping effect (DIP), while group II included 31 patients with the nondipping phenomenon (NDIP). All subjects had FA gas chromatography and inflammatory metabolite measurements performed with the use of liquid chromatography, their 24 h blood pressure was recorded, and they were assessed with the Epworth sleepiness scale (ESS). Results: In the nondipping group a higher level of C16:0 palmitic acid was observed, while lower levels were observed in regard to C20:0 arachidic acid, C22:0 behenic acid and C24:1 nervonic acid. A decreased leukotriene B4 level was recorded in the nondipping group. None of the FAs and derivatives correlated with the ESS scale in the group of patients after stroke. Correlations were observed after dividing into the DIP and NDIP groups. In the DIP group, a higher score of ESS was correlated with numerous FAs and derivatives. Inflammation of a lower degree and a higher level of anti-inflammatory mediators from EPA and DHA acids favored the occurrence of the DIP. A high level of C18: 3n6 gamma linoleic acid indicating advanced inflammation, intensified the NDIP effect. Conclusions: We demonstrated potential novel associations between the FA levels and eicosanoids in the pathogenesis of the nondipping phenomenon. There are common connections between fatty acids, their metabolites, inflammation, obstructive sleep apnea syndrome and nondipping in stroke patients.

Acute coronary syndrome (ACS) is a set of signs and symptoms caused by a reduction of coronary blood flow with subsequent myocardial ischemia. ACS is associated with activation of the leukotriene (LT) pathway with subsequent releases of various LTs, including LTB4, LTC4, and LTD4, which cause inflammatory changes and induction of immunothrombosis. LTs through cysteine leukotriene (CysLT) induce activation of platelets and clotting factors with succeeding coronary thrombosis. CysLT receptor (CysLTR) antagonists such as montelukast (MK) may reduce the risk of the development of ACS and associated complications through suppression of the activation of platelet and clotting factors. Thus, this critical review aimed to elucidate the possible protective role of MK in the management of ACS. The LT pathway is implicated in the pathogenesis of atherosclerosis, cardiac hypertrophy, and heart failure. Inhibition of the LT pathway and CysL1TR by MK might be effective in preventing cardiovascular complications. MK could be an effective novel therapy in the management of ACS through inhibition of pro-inflammatory CysLT1R and modulation of inflammatory signaling pathways. MK can attenuate thrombotic events by inhibiting platelet activation and clotting factors that are activated during the development of ACS. In conclusion, MK could be an effective agent in reducing the severity of ACS and associated complications. Experimental, preclinical, and clinical studies are recommended to confirm the potential therapeutic of MK in the management of ACS.